Kaposi's sarcoma, the most prevalent malignancy in AIDS patients, is characterized by proliferating spindle cells of endothelial cell (EC) origin, infiltration by inflammatory cells and the presence of the KS herpesvirus (KSHV) in lesions. The ultimate goal of our work is to understand how viral immune evasion mechanisms contribute to viral pathogenesis and the d evelopment of KS. We focus on the function of two closely related open reading frames, K3 and K5. These proteins, aka MIR1 and MIR2, are viral homologs of the cellular membrane-associated RI NG-CH (MARCH) protein family comprising transmembrane ubiquitin Ii gases that recruit cellular ubiquitin-conjugating enzymes for degradation of transmembrane proteins. While K3 predominantly targets host proteins invovled in alerting the cellular immune system, our work revealed that K5 substrates include EC-specific adhesion molecules (ALCAM, CD3IIPECAM, VE-Cadherin, alpha and beta- Catenin) and the interferon-induced antiviral protein B ST2/Tetherin. We therefore hypothesize that K5 modulates innate immune defense as well as angioproliferative and inflammatory processes during KS development. Specifically, we will address two major questions: 1) What are the consequences of K5 expression for the function of KSHV-infected ECs and their interaction with innate immune cells? Using ECbased in vitro models of KS we will examine the modulation of EC/EC and EC/leukocyte adhesion by KSHV. 2) Why and how does KSHV eliminate BST2/Tetherin? Preliminary data show that K5 ubiquitinates and degrades BST2/Tetherin which tethers enveloped viral particles to host cell membranes. We will examine the hypothesis that K5 counteracts the inhibition of KSHV egress by BST2. Upon completion of these studies we will have a better understanding of viral modulation of host processes that are expected to be central to the establishment and maintenance of longterm infection in healthy individuals and KS development in the immunocompromised.